JP2015203011A - Novel polymorph of brimonidine tartrate and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel polymorph of brimonidine tartrate and a production method thereof.SOLUTION: By suspending brimonidine tartrate technical product in acetone and purifying the suspension, a crystalline form brimonidine tartrate having a melting point of 199 to 205°C is obtained.

Description

  The present invention relates to a novel polymorph of brimonidine tartrate and a method for producing the same.

  Brimonidine [chemical name: 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxalin-6-amine] is known to be useful as a cardiovascular regulator. . For example, in Japanese Patent Laid-Open No. 56-25176 (Patent Document 1), a benzene solution of 5-bromo-6-isothiocyanatoquinoxaline is added to a benzene solution of ethylenediamine and stirred to separate a lower oily substance. Washed, dissolved in methanol, refluxed until the release of hydrogen sulfide ceased, concentrated, and the resulting precipitate was collected by filtration and recrystallized from methanol to synthesize brimonidine with a melting point of 250-251 ° C. An example is given. This document describes that the obtained brimonidine is useful as an antihypertensive agent.

  As pharmaceutical use of brimonidine, uses other than the above-mentioned medicine are also known. For example, Japanese Patent No. 2999240 (Patent Document 2) describes a method for reducing or maintaining intraocular pressure by directly administering brimonidine to a mammalian eye, and is useful for the treatment of glaucoma. Have been described. In the example of this document, the reaction product was collected by filtration from the reaction solution of 5-bromo-6-isothiocyanatoquinoxaline and ethylenediamine as in the example of Patent Document 1, and then dried under reduced pressure, with a melting point of 242 to 244. A crude product at 0 ° C. is prepared, the crude product is purified by an acid-base extraction method, a purified product having a melting point of 249-250 ° C. is prepared, and the purified product is recrystallized from N, N-dimethylformamide Describes an example of synthesis of brimonidine having a melting point of 252 to 253 ° C.

  Patent Documents 1 and 2 describe acid addition salts of quinoxaline derivatives such as brimonidine, and tartaric acid salt as an example. This tartrate salt is sold as a therapeutic agent for glaucoma and ocular hypertension after a pharmacological approval test. For example, Aifagan (registered trademark) ophthalmic solution 0.1% package insert (Non-Patent Document 1) describes an aqueous eye drop containing brimonidine tartrate at a concentration of 1 mg / mL. The 1% pharmaceutical interview form (Non-Patent Document 2) describes that the melting point of brimonidine tartrate is 207 to 210 ° C. as the physicochemical properties of the active ingredient.

  However, these references do not describe any polymorphs of brimonidine tartrate.

JP-A-56-25176 (Claims, Examples, page 5, upper right column, lines 10 to 11) Patent No. 2999240 (Claims, Examples)

AIFAGAN (registered trademark) ophthalmic solution 0.1% package insert, January 2012 Aifangan (registered trademark) ophthalmic solution 0.1% pharmaceutical interview form, April 2012

  Accordingly, an object of the present invention is to provide a novel polymorph of brimonidine tartrate and a method for producing the same.

  Another object of the present invention is to provide a novel polymorph of brimonidine tartrate having high stability and excellent powder flowability, and a method for producing the same.

  As a result of diligent studies to achieve the above-mentioned problems, the present inventor suspended brimonidine tartaric acid in acetone, and purified (sustained or crystal grown) the suspension, thereby making brimonidine different from conventional crystals. The inventors have found that a new polymorph of tartrate salt can be obtained, and that this new polymorph is excellent in stability and powder flowability, thereby completing the present invention.

  That is, the present invention includes crystalline brimonidine tartrate having a melting point at 199 to 205 ° C. (for example, 200 to 204 ° C.) (hereinafter sometimes referred to as A-form crystals and A-form brimonidine tartrate). Crystalline brimonidine tartrate has a peak intensity at a diffraction angle (2θ) of 11.87 ° of 5 or more when the peak intensity at a diffraction angle (2θ) of 34.3 ° is 1 in a powder X-ray diffraction spectrum. The peak intensity at a diffraction angle (2θ) of 12.48 ° may be 1.7 or more, and the peak intensity at a diffraction angle (2θ) of 20.04 ° may be 1.8 or more.

  Brimonidine tartrate may be a mixture of brimonidine tartrate containing Form A crystals. For example, the brimonidine tartrate mixture may be a mixture of Form A brimonidine tartrate and other polymorphs (polymorphs of brimonidine tartrate including amorphous). Further, when the average particle size of the A-type crystal is 20 μm or more, the powder fluidity can be greatly improved.

  The present invention includes a pharmaceutical composition comprising Form A brimonidine tartrate and a pharmacologically acceptable carrier. The present invention also includes a preventive and / or therapeutic agent for eye diseases (for example, glaucoma, ocular hypertension) containing A-form brimonidine tartrate as an active ingredient. Furthermore, the present invention includes a method for producing a crystalline brimonidine tartrate salt (form A crystal), which comprises a step of suspending a brimonidine tartrate bulk in acetone and purifying the suspension (standing or crystal growth).

  In the present specification, “brimonidine tartrate” has the chemical name 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxalin-6-amine mono- (2R, 3R). ) -Refers to a compound that is a tartrate salt.

  In the present invention, compared to conventional crystals, the stability is high and the powder flowability is excellent.

FIG. 1 is a graph showing the results of the photostability test of Example 1 and Comparative Example 1. FIG. 2 is a graph showing the relationship between the average particle diameter and the angle of repose for A-form brimonidine tartrate.

[Type A brimonidine tartrate]
Form A brimonidine tartrate of the present invention is characterized by powder X-ray diffraction spectrum and / or differential scanning calorimetry spectrum, and form A brimonidine tartrate has a melting point of, for example, 199 to 205 ° C, preferably 200 to 204 ° C. It may be about (for example, 202 ± 1 ° C.).

Crystalline brimonidine tartrate (A-form crystal) has a diffraction angle when the peak intensity (peak height) I ₀ at a diffraction angle (2θ) of 34.3 ° is “1” in the powder X-ray diffraction spectrum. (2θ) The peak intensity I ₁ at 11.87 ° is 5 or more (for example, 5 to 20), preferably 7 to 15 (for example, 8 to 12), more preferably 9 to 11.5 (for example, 10 to 10). The peak intensity I ₂ at the diffraction angle (2θ) of 12.48 ° is 1.7 or more (eg, 1.7 to 3.5), preferably 1.8 to 3 .2 (for example, 2 to 2.8) or so; the peak intensity I ₃ at the diffraction angle (2θ) of 20.04 ° is 1.8 or more (for example, 1.8 to 5), preferably 2-4 (for example, 2.5-3.5) may be sufficient. The peak intensity ratio I ₁ / I ₀ is 10.7 ± 0.5, the peak intensity ratio I ₂ / I ₀ is 2.4 ± 0.5, and the peak intensity ratio I ₃ / I ₀ is 2.9 ± 0.5. It may be a degree. Crystalline brimonidine tartrate (form A crystals) has relatively high peak intensities I ₁ and I ₃ compared to the original brimonidine tartrate salt.

  The melting point can be measured using a differential scanning calorimeter (DSC) under conditions of a heating rate of 10 ° C./min. The melting point may be measured using a capillary.

  The powder X-ray diffraction spectrum was measured using a conventional X-ray diffractometer under the conditions of a source Cu K (α1), tube voltage 40 kV, tube current 40 mA, sampling interval 0.1 °, and scan rate 10 ° / min. It can be measured. The angle 2θ indicating the diffraction peak may vary slightly depending on the sample state or the like. However, if the crystal structure is the same, the number of characteristic diffraction peaks and the relative intensity do not change greatly, and almost the same diffraction Indicates a pattern.

  The crystalline form of brimonidine tartrate may be single crystal, twin crystal, or polycrystalline. The form (external shape) of the crystalline brimonidine tartrate is not particularly limited, and for example, triclinic, monoclinic, orthorhombic (tetragonal), tetragonal, cubic, trigonal (rhombohedral), hexagonal It may be a crystal, a spherulite, a body crystal, a bark crystal, a needle crystal (for example, a beard crystal), or the like.

  Form A crystals are stable to heat and / or light. That is, even when heated at 100 ° C. for 7 days or more and the purity is measured by HPLC, the purity hardly deteriorates (maintaining a purity of 99.5% or more) and is stable against heat. Further, even when ultraviolet light (wavelength: 254 nm) is irradiated on a petri dish and the purity is measured by HPLC in the same manner as described above, the purity is hardly reduced and is stable to light. Thus, since it is stable to heat and light, it is possible to provide a pharmaceutical that can eliminate the reduction of active ingredients due to long-term storage and can exhibit its medicinal effects stably.

  The present invention also discloses mixtures comprising Form A brimonidine tartrate and other polymorphs (crystals other than Form A and / or amorphous brimonidine tartrate). That is, Form A brimonidine tartrate is present in the form of a mixture in combination with a conventional crystalline polymorph (referred to as Form B crystal) and / or amorphous brimonidine tartrate), for example, in the form of a physical mixture, mixed crystal, or the like. It may be. A mixture containing Form A brimonidine tartrate appears to have improved stability and fluidity. The weight ratio of the A-form crystal to other polymorphs (such as the B-form crystal and / or amorphous brimonidine tartrate) can be selected from the range of about 1/99 to 99/1. For example, 10/90 to 98 / 2 (for example, 20/80 to 95/5), preferably 30/70 to 90/10 (for example, 40/60 to 85/15), more preferably about 50/50 to 80/20. Good. The above-mentioned weight ratio shows the peak intensity (peak height) or integrated intensity (peak area) at 2θ = 11.8 ° in the powder X-ray diffraction spectrum when the form A crystal form brimonidine tartrate alone and the form A brimonidine tartrate. And other polymorphic brimonidine tartrate mixtures.

  The average particle size (volume average particle size, etc.) of the A-form crystal is 20 μm or more (for example, 20 to 2000 μm), preferably 23 μm or more (for example, 23 to 1000 μm), more preferably 25 μm or more (for example, 25 to 800 μm). It may be about 20 to 100 μm (for example, 25 to 70 μm). If the average particle size is too small, the flowability of the powdered brimonidine tartrate is extremely low, and in the preparation of a preparation containing a small amount of brimonidine tartrate, the content of the active ingredient varies greatly. For example, the angle of repose of conventional powdered brimonidine tartrate is about 70 ° with an average particle size of about 3 to 5 μm, about 60 ° with an average particle size of about 10 μm, and flows in a voluminous feeling. Therefore, a preparation containing brimonidine tartrate with a small amount of active ingredient (for example, an eye drop containing brimonidine tartrate at a concentration of 1 mg / mL) is used to measure a relatively large amount of active ingredient and to produce a large amount of liquid carrier. If it is not diluted with, eye drops having a low active ingredient concentration cannot be prepared. Therefore, brimonidine tartrate having poor powder flowability is not suitable for preparing a low concentration active ingredient (such as eye drops) in a small lot by automatic weighing.

  In the present invention, an A-type crystal having an average particle diameter of 20 μm or more has high powder fluidity and an angle of repose of, for example, about 45 ° or less, and the fluidity is significantly improved specifically. Therefore, even if the preparation has a very low concentration of the active ingredient, the preparation can be prepared in a small lot by automatic weighing. The angle of repose of the A-type crystal of the present invention may be, for example, about 45 to 20 ° (for example, 45 to 25 °), preferably about 40 to 20 ° (for example, 37 to 25 °). By simply changing the average particle size from 10 μm to 20 μm, the fluidity is greatly improved from an angle of repose of about 63 to 67 ° (for example, 65 °) to about 43 to 47 ° (for example, 45 °).

  In addition, the average particle diameter and particle size distribution of powdery brimonidine tartrate can be measured by a conventional method, for example, a laser diffraction particle size distribution measuring apparatus.

[Method for producing crystalline brimonidine tartrate]
The method for producing Form A brimonidine tartrate includes, for example, a suspension step of suspending the original brimonidine tartrate salt in acetone, and a step of purifying (standing or crystal growth) the suspension obtained in this suspension step. Contains.

  Brimonidine tartrate bulk is prepared by reacting 6-amino-5-bromoquinoxaline with thiophosgene to form 5-bromo-6-isothiocyanatoquinoxaline, and reacting this isothiocyanate with ethylenediamine. To form 5-bromo-6- [N- (2-aminoethyl) thioureido] quinoxaline and the thioureido compound may be prepared by cyclization in the presence of tartaric acid. For details of the method for preparing brimonidine tartrate raw material, reference can be made to JP-A-56-25176.

  In the suspending step, the ratio (amount used) of acetone is, for example, 0.1 to 7.5 mL, preferably 0.3 to 2.5 mL, more preferably 0.5 to 1 g of brimonidine tartrate bulk. About 1.5 mL.

  The purification method is not limited as long as impurities in the active ingredient can be eluted, and the suspension is, for example, 5 to 40 ° C. (for example, 10 to 35 ° C.), preferably 15 to 30 ° C. (for example, 20 to 30 ° C.). ), Particularly at room temperature (for example, 15 to 25 ° C.) and may be stirred and stirred. In order to form a stable crystal form, it is preferable to stand after stirring. The standing time may be, for example, 3 to 60 hours (for example, 6 to 45 hours, particularly 12 to 36 hours). Crystals purified in this manner can be obtained by separation by filtration, centrifugation, etc., and drying. The purification may be performed only once or may be repeated a plurality of times (for example, 2 to 4 times). When the purification is repeated, each purification method may be the same as or different from each other. The recovered crystal may be pulverized if necessary, but it is preferable not to apply an excessive shearing force in order to suppress a decrease in crystallinity. An A-type crystal can be formed by such a method.

  In the production method of Form A brimonidine tartrate, crystals of Form A can be prepared without mixing other polymorphs (such as amorphous), but even if a mixture containing other polymorphs (amorphous) is prepared. Good. Furthermore, you may mix A form crystal | crystallization and an amorphous brimonidine tartrate in the said ratio.

Form A brimonidine tartrate of the present invention is useful as an adrenergic α ₂ receptor agonist, and can be suitably used as, for example, a sedative or analgesic agent, an antihypertensive agent, a prophylactic and / or therapeutic agent for ocular diseases. Examples of eye diseases include glaucoma (such as open-angle glaucoma), neurodegeneration, and ocular hypertension.

  Brimonidine tartrate may be used alone as a medicine, or may be used as a combined medicine in combination with other active ingredients (physiologically active ingredients or pharmacologically active ingredients) as necessary. Other active ingredients include vitamins (vitamin A such as retinol or a salt thereof; vitamin B such as thiamine or a salt thereof; vitamin E such as tocopherol or a salt thereof), amino acids (aspartic acid or a salt thereof) ), Dry eye therapeutic agents (such as hyaluronic acid or salts thereof), glaucoma therapeutic agents (beta-blockers such as timolol or salts thereof), prostaglandin-related drugs such as unoprostone, latanoprost, travoprost, or salts thereof; brinzolamide, Carbonic anhydrase inhibitors such as dorzolamide or their salts), cataract treatment agents (such as pirenoxine, glutathione or their salts), antibacterial agents (ofloxacin, levofloxacin, norfloxacin, lomefloxacin, gatifloxacin, tosufloxacin, moxifloxacin) or Etc. These salts), antiallergic agents (cromoglycate, ketotifen, pemirolast, tranilast, ibudilast, acitazanolast, levocabastine, olopatadine, glycyrrhizinate, lysozyme, amlexanox, azulene, cyclosporin or the like salt thereof), and others. The proportion of the other active ingredient is, for example, 30 parts by weight or less, preferably 20 parts by weight or less, more preferably 10 parts by weight or less (for example, 0.01 to 5 parts by weight) with respect to 100 parts by weight of brimonidine tartrate. Degree.

  Brimonidine tartrate may be used as a pharmaceutical composition (or formulation) in combination with a carrier (such as a pharmacologically acceptable carrier). In the pharmaceutical composition of the present invention, the carrier is appropriately selected according to the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation). The dosage form is not particularly limited, and is a solid preparation (powder, powder, granule (granule, fine granule, etc.), pill, pill, tablet, capsule (soft capsule, hard capsule, etc.), dry syrup, Suppositories, etc.), semi-solid preparations (creams, ointments, gels, gummies, film preparations, sheet preparations, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions) , Injections, drops, etc.). Also included are sprays such as the powders and / or liquids, aerosols and the like. The capsule may be a liquid-filled capsule or a capsule filled with a solid agent such as a granule. The preparation may be a lyophilized preparation. Furthermore, the preparation of the present invention may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation). The preparations are oral preparations (eg granules, powders, tablets (sublingual tablets, orally disintegrating tablets, etc.), capsules, syrups, emulsions, suspensions, jellies, gummies, film preparations, etc.). Alternatively, it may be a parenteral preparation (inhalation agent, transdermal absorption agent, eye drop, nasal drop, ear drop etc.). Furthermore, the preparation may be a topical preparation [injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), suspension, ointment, patch, cataplasm] Good.

  Examples of the carrier include Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Encyclopedia 2007” (Pharmaceutical Daily Inc., 2007) Issued in July), (3) Pharmacy, revised 5th edition, Nanedo Co., Ltd. (1997) and (4) Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily Inc., August 2003) It can be selected according to the administration route and the pharmaceutical application.

  In many cases, at least one carrier selected from excipients, binders and disintegrants is used as the carrier for the solid preparation.

  Examples of excipients include sugars such as lactose, glucose, sucrose, mannitol, sorbitol, and xylitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxide and silicate.

  As a binder, soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as gum arabic, dextrin and sodium alginate; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carboxyvinyl polymer, polyacrylic acid type Synthetic polymers such as polymers, polylactic acid and polyethylene glycol; methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( Examples thereof include cellulose ethers such as HPMC).

  Examples of the disintegrant include carboxymethyl starch sodium, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose.

  Among oil carriers, oily carriers include animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil, and cottonseed oil; animal oils such as squalane) and mineral oils (liquid paraffin, silicone oil, etc.) Etc. can be exemplified. Examples of the aqueous carrier include water (sterilized purified water or distilled water), physiological saline, Ringer's solution, glucose solution, water-soluble organic solvents (e.g., lower aliphatic alcohols such as ethanol and isopropanol), and the like.

The semi-solid preparation carrier may be selected from the solid preparation carrier and / or the liquid carrier. The carrier of the semisolid preparation may contain a lipid. Lipids include waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), higher fatty acids (saturated or unsaturated fatty acids such as stearic acid and oleic acid), higher fatty acid esters (saturated or unsaturated fatty acid alkyl esters). , Esters of saturated or unsaturated fatty acids and polyhydric alcohols (poly C _2-4 alkylene glycol, glycerin, etc.), hardened oils, higher alcohols (saturated or unsaturated fatty alcohols such as stearyl alcohol, oleyl alcohol, etc.) And metal soaps (fatty acid metal salts such as coconut oil fatty acid sodium and calcium stearate).

  In the said pharmaceutical composition (or formulation), a well-known additive can be used suitably according to an administration route, a dosage form, etc. Examples of such additives include lubricants, disintegration aids, emulsifiers, dispersants, suspending agents, solvents, solubilizers, thickeners, pH adjusters, buffers, stabilizers, or preservatives. , Fungicides or antibacterial agents, antistatic agents, flavoring agents or masking agents, coloring agents, flavoring agents or fragrances, cooling agents, antifoaming agents, isotonic agents, soothing agents, and the like. These additives can be used alone or in combination of two or more. Examples of the liquid additive include a pH adjuster, a buffer, a stabilizer, a thickener, and an isotonic agent.

  Examples of pH adjusters include bases (alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate), acids (organic acids such as acetic acid and citric acid; hydrochloric acid) And inorganic acids).

  Examples of the buffer include boric acid buffers (boric acid, borax, etc.), phosphate buffers (phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) and the like.

  Examples of the stabilizer include sodium edetate and sodium bisulfite.

  Examples of the thickener include methyl cellulose, carmellose, carmellose sodium, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, chondroitin sulfate, sodium chondroitin sulfate, and pullulan.

  Isotonic agents include sugars (sorbitol, glucose, mannitol, etc.), polyhydric alcohols (glycerin, polyethylene glycol, propylene glycol, etc.), inorganic salts (sodium chloride, potassium chloride, magnesium chloride, calcium chloride, etc.), etc. It can be illustrated.

  Typical pharmaceutical compositions include solutions, semi-solid preparations and the like, and in particular, ophthalmic liquids (such as eye drops such as aqueous eye drops), ophthalmic semi-solid preparations (such as eye ointments) and the like can be exemplified. .

  The proportion (content) of brimonidine tartrate is, for example, 100 parts by weight or less, preferably 0.01 to 90 parts by weight (eg 0.05 to 80 parts by weight), more preferably about 0.1 to 50 parts by weight (for example, 0.15 to 30 parts by weight). Even if the proportion of brimonidine tartrate is small, it can exert a high pharmacological effect, improve patient compliance, and have few side effects and excellent safety.

  The pharmaceutical composition of the present invention is prepared by a conventional formulation method, for example, a production method described in the 16th revised Japanese Pharmacopeia or this production method, using an active ingredient, a carrier component, and if necessary an additive. Can be prepared by different methods.

Brimonidine tartrate salt of the invention (pharmaceutical composition, adrenergic alpha ₂ receptor agonists, including the prevention and / or therapeutic agent for eye diseases) has low toxicity, is excellent also its safety, human and non-human animals Usually, it is safely administered to mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.). The dose can be appropriately selected depending on the species, age, weight and condition (general condition, medical condition, presence of complications, etc.), administration time, dosage form, administration method and the like of the administration target. In the present invention, a high therapeutic effect can be obtained even with a small dose. The frequency of administration is not particularly limited, and may be, for example, once a day, or may be multiple times a day (for example, 2 to 3 times) as necessary.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[Powder X-ray diffraction spectrum]
The powder X-ray diffraction spectrum was measured using a powder X-ray diffractometer (manufactured by Rigaku Corporation, sample horizontal X-ray diffractometer Ultima IV), source: Cu K (α1), tube voltage: 40 kV, tube current: 40 mA. , Sampling interval: 0.1 °, scan rate 10 ° / min. In the powder X-ray diffraction chart, the diffraction peak was searched by the second derivative method with the peak width threshold being 0.1 °.

[Differential scanning calorimetry]
Using a differential scanning calorimeter (model: DSC8530L), differential heat and thermogravimetry were measured simultaneously under the conditions of a temperature rising rate of 10 ° C./min.

[Average particle size and particle size distribution]
Using a laser diffraction particle size distribution analyzer (model: LDSA-1400A), the particle size distribution of the granular brimonidine tartrate was measured, and the average particle size (volume average particle size) was calculated.

[Angle of repose]
The height from the bottom of the funnel to the deposition surface (horizontal upper surface of a cylinder with a diameter of 1.5 cmφ) is fixed at 4.5 cm, and the powdered sample naturally falls on the upper surface of the cylinder. The powder sample was dropped, and the angle from the upper surface of the cylinder to the conical ridge was measured to obtain the angle of repose. When the powder sample was asymmetrically deposited on the upper surface of the cylinder, a larger angle was taken as the repose angle.

Comparative Example 1
Brimonidine tartrate raw material (Amatek Chemical Co.ltd., B-form crystal) was used. The melting point by differential scanning calorimetry was 207-210 ° C. Moreover, the average particle diameter of the raw material was 3.8 μm.

Example 1 (A-type crystal)
Brimonidine tartrate drug substance (50 mg) was mixed with acetone (1.00 mL) and allowed to stand at room temperature (20 ° C.) for 20 hours. The produced crystals were suction filtered with a glass filter, left to stand at room temperature for 3 days, dried, and ground in a mortar for about 1 minute to obtain brimonidine tartrate form A crystals (43 mg). Differential melting calorimetry showed a melting point of 200.4-203.5 ° C. The average particle size of the obtained crystals was 22 μm.

  Further, except for adjusting the grinding time between 10 to 60 seconds, the A-type crystals of brimonidine tartrate are ground in the same manner as described above, and the A-types having average particle sizes of 1063 μm, 517 μm, 318 μm, 221 μm and 91 μm are obtained. Crystals were obtained respectively.

Test Example 1: Light Stability Test Table 1 shows ultraviolet rays (wavelength: 254 nm, irradiation distance: 15 cm, room temperature) for the compound of Example 1 and the compound of Comparative Example 1 using an ultraviolet irradiation device (manufactured by SPECTRONICS). Continued to be irradiated for At each time, the compound of Example 1 and the compound of Comparative Example 1 were sampled, dissolved in water to prepare a sample solution, purity was measured by HPLC (measurement wavelength: 280 nm), and light stability was examined. The results are shown in Table 1 and FIG.

  As is clear from Table 1, the Brimonidine purity in Comparative Example 1 is greatly reduced as compared with Example 1. In particular, after 120 days, the purity of Comparative Example 1 was 5% lower than that of Example 1, indicating that Example 1 is very stable to light.

Test Example 2: Fluidity Test The angle of repose of the crystal particles obtained in Comparative Example 1 and Example 1 was measured three times, and the average value was calculated. The results shown in Table 2 and FIG. 2 were obtained. For reference, the degree of fluidity is extracted from JP reference information (G2 physical properties-related powder fluidity).

  As is apparent from Table 2 and FIG. 2, the powder A-form crystal brimonidine tartrate is very poor in fluidity in Comparative Example 2 where the average particle diameter is small, whereas the fluidity is present at an average particle diameter of 20 μm or more. It is improved rapidly.

Formulation Example 1
According to the following formulation, brimonidine tartrate salt obtained in Example 1 (average particle size 22 μm) and carrier component are mixed, this mixture is granulated by a dry granulation method, and this granulated product is sized. As a result, granules were obtained.

[Prescription]
Brimonidine tartrate 10mg
Crystalline cellulose 780mg
Sodium carboxymethyl starch 100mg
Glycerin fatty acid ester 100mg
Talc 10mg
Total amount 1000mg
Formulation Example 2
The granules obtained in Formulation Example 1 were filled into No. 0 capsules to obtain capsules.

Formulation Example 3
According to the following prescription, the granule obtained in Preparation Example 2 and the carrier component were mixed and tableted to obtain a tablet.

[Prescription]
100 mg of granules obtained in Formulation Example 2
Crystalline cellulose 172mg
Glycerin fatty acid ester 20mg
Talc 4mg
Light anhydrous silicic acid 4mg
Total amount 300mg
Formulation Example 4
In accordance with the following formulation, the brimonidine tartrate obtained in Example 1 and the additive are added to sterilized purified water, the solution is adjusted to a predetermined osmotic pressure and pH, filtered and sterilized in an aseptic environment, and washed and sterilized. An ophthalmic solution was obtained by aseptic filling into a used container.

Brimonidine tartrate 0.1g
Anhydrous sodium dihydrogen phosphate 0.56g
Sodium monohydrogen phosphate 0.28g
Sodium chloride 0.26g
Benzalkonium chloride 0.005g
Sterile purified water was added to make a total volume of 100 mL.

Formulation Example 5
According to the following formulation, the brimonidine tartrate obtained in Example 1 and the base were added, adjusted to a predetermined viscosity, and aseptically filled into a container that had been washed and sterilized in an aseptic environment to obtain an eye ointment. .

0.1 g brimonidine tartrate obtained in the examples
80g white petrolatum
Liquid paraffin 19.9g
Total amount 100g

  The brimonidine tartrate of the present invention is useful as a preventive and / or therapeutic agent for various diseases because it has excellent bioavailability such as cell membrane permeability and can be easily transferred to a living tissue. In particular, the present invention is useful as a prophylactic and / or therapeutic agent for eye diseases (such as glaucoma and ocular hypertension).

Claims (7)

  Crystalline brimonidine tartrate having a melting point at a temperature of 199 to 205 ° C.   In the powder X-ray diffraction spectrum, when the peak intensity at the diffraction angle (2θ) of 34.3 ° is 1, the peak intensity at the diffraction angle (2θ) of 11.87 ° is 5 or more, and the diffraction angle (2θ) of 12 2. The crystalline brimonidine tartrate salt according to claim 1, having a peak intensity at .48 ° of 1.7 or more and a peak intensity at diffraction angle (2θ) of 20.04 ° of 1.8 or more.   The crystalline brimonidine tartrate salt according to claim 1 or 2, which is in a powder form having an average particle size of 20 µm or more.   A pharmaceutical composition comprising the brimonidine tartrate according to any one of claims 1 to 3 and a pharmacologically acceptable carrier.   A prophylactic and / or therapeutic agent for eye diseases comprising the brimonidine tartrate according to any one of claims 1 to 3 as an active ingredient.   The preventive and / or therapeutic agent according to claim 5, wherein the eye disease is at least one disease selected from glaucoma and ocular hypertension.   The method for producing crystalline brimonidine tartrate according to any one of claims 1 to 3, comprising a step of suspending a brimonidine tartrate bulk in acetone and purifying the suspension.

Images